Perforated bioabsorbable oil film and methods for making the same

ABSTRACT

A bio-absorbable stand-alone film is derived at least in part from fatty acids. The bio-absorbable stand-alone film can have anti-adhesive, anti-inflammatory, non-inflammatory, and wound healing properties, and can additionally include one or more therapeutic agents incorporated therein. The stand-alone film has one or more perforations or depressions formed therein. Corresponding methods of making the bio-absorbable stand-alone film with one or more perforations or depressions include molding, cutting, carving, puncturing or otherwise suitable methods to create the perforations or depressions in the bio-absorbable stand-alone film. The resulting stand-alone film is bioabsorbable.

RELATED APPLICATION

This application is a continuation in part of co-pending U.S. patentapplication Ser. No. 11/237,264, filed on Sep. 28, 2005, which claimspriority to, and the benefit of, U.S. Provisional Application No.60/613,808, filed on Sep. 28, 2004. This application also relates toco-pending U.S. patent application Ser. No. 11/237,420, filed on Sep.28, 200, U.S. Provisional Application No. 60/726,869, filed on Oct. 14,2005, and co-pending U.S. patent application Ser. No. ______ (AttorneyDocket No. ATA-457), filed concurrently with this application on Sep.22, 2006. The disclosure of the above-mentioned applications is herebyincorporated by reference herein in its entirety.

FIELD OF THE INVENTION

The present invention generally relates to bioabsorbable bio-absorbablestand-alone films, and more particularly to perforated bioabsorbablebio-absorbable stand-alone films.

BACKGROUND OF THE INVENTION

Different surgical procedures often make use of a method referred to asblunt dissection. Blunt dissection can be generally described asdissection accomplished by separating tissues along natural cleavagelines without cutting. Blunt dissection is executed using a number ofdifferent blunt surgical tools, as is understood by those of ordinaryskill in the art. Blunt dissection is often performed in cardiovascular,colorectal, urology, gynecology, upper GI, and plastic surgeryapplications, among others.

In accordance with several methods of blunt dissection, a small incisionis made in the patient. Specially designed blunt dissection tools havingsmall profiles are inserted through the incision to the desired locationin the body. Longer tools may be used to access locations substantiallydistal from the incision, while shorter tools can be used to accesslocations closer to the incision.

After the blunt dissection separates the desired tissues into separateareas, there is often a need to maintain the separation of thosetissues. In fact, post surgical adhesions can occur following almost anytype of surgery, resulting in serious postoperative complications.Adhesions may cause intestinal obstruction, bowel torsion, pain andinfertility following general abdominal and pelvic surgery. Adhesionscan also develop following orthopedic and cardiac surgery. Surgicaladhesion disease is a complex inflammatory disease in which tissues thatnormally remain separated in the body grow into each other as a resultof surgical trauma. Conventional surgical methods make use ofanti-adhesion barriers, such as INTERCEED from Johnson & Johnson orSEPRAFILM from Genzyme Corporation.

INTERCEED is a fabric relatively easy to apply and handle. However,effectiveness may be diminished when bleeding has not been completelycontrolled. SEPRAFILM is widely used in general surgery. However, it ischallenging for surgeons to apply and handle because of the film'stendency to easily break apart upon exposure to water due to theirchemical make up and bio-dissolvable properties. The composition andstructural properties of these bio-dissolvable products require thatthey be handled with dry hands or instruments, which can be difficultduring most surgical intervention operations. Furthermore, many of thesebio-dissolvable films are made intentionally thin to minimize tissuedisruption and consequently end up being structurally weak (i.e., easilytorn or folded during handling). In addition, SEPRAFILM is composed oftwo chemically modified biopolymers, sodium hyaluronate (HA) andcarboxymethylcellulose (CMC), reacted with an activating agent1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC) toform a water insoluble powder, hyaluronic acid-carboxymethylcellulose(HA-CMC). Although it is biodegradable, some of its breakdown products,such as smaller CMC units and ethyl-(3-dimethylaminopropyl)-urea (EDU),are not consumable by the patient's cell tissues. Hence, biodegradablesubstances, such as polymers, can cause inflammatory response due toeither the parent substance or those substances formed during breakdown,and they may or may not be absorbed by tissues.

Another drawback of most barrier films is their non-elastic propertiesdue to their sheet-like construction. In other words, the barrier filmsare not mechanically stretchable. Hence, it is difficult to use thebarrier films to conform to three-dimensional surface of a tissue.

SUMMARY OF THE INVENTION

The present invention relates to a bio-absorbable stand-alone film thathas one or more perforations or depressions provided in the filmstructure, and the corresponding method of making. The perforations inthe bio-absorbable stand-alone film allow the film to expand and conformto a three-dimensional surface of a tissue, even in embodiments wherethe bio-absorbable film itself is not elastic. The bio-absorbablestand-alone film is generally formed of a naturally occurring oil, or anoil composition formed in part of a naturally occurring oil. Inaddition, the oil composition can include a therapeutic agent component,such as a drug or other bioactive agent. The perforations in thebio-absorbable film can speed up the biological absorption of the filmby allowing body fluids to contact a greater amount of surface area ofthe film compared to a film without perforations. The bio-absorbablestand-alone film is implantable in a patient for short term or long termapplications. As implemented herein, the bio-absorbable stand-alone filmis a non-polymeric cross-linked gel derived at least in part from afatty acid compound.

It should be noted that the term cross-linked gel, as utilized hereinwith reference to the present invention, refers to a gel that isnon-polymeric and is derived from an oil composition comprisingmolecules covalently cross-linked into a three-dimensional network byone or more of ester, ether, peroxide, and carbon-carbon bonds in asubstantially random configuration. In various preferred embodiments,the oil composition comprises a fatty acid molecule, a glyceride, andcombinations thereof.

In accordance with one embodiment of the present invention, abio-absorbable stand-alone film includes a film structure having a firstside and a second side and formed of a non-polymeric cross-linked gelmaterial formed at least in part of a fatty acid compound or derivativeor analog thereof, and one or more perforations provided in the filmstructure.

In accordance with aspects of the present invention, the fatty acidcompound includes omega-3 fatty acid, fish oil fatty acid, free fattyacid, triglycerides, esters of fish oil, or a combination thereof. Thefish oil fatty acid can include one or more of arachidic acid, gadoleicacid, arachidonic acid, eicosapentaenoic acid, docosahexaenoic acid orderivatives, analogs and pharmaceutically acceptable salts thereof. Thefree fatty acid can include one or more of butyric acid, caproic acid,caprylic acid, capric acid, lauric acid, myristic acid, palmitic acid,palmitoleic acid, stearic acid, oleic acid, vaccenic acid, linoleicacid, alpha-linolenic acid, gamma-linolenic acid, behenic acid, erucicacid, lignoceric acid, analogs and pharmaceutically acceptable saltsthereof.

In accordance with further aspects of the present invention, thebio-absorbable stand-alone film further includes a vitamin E compoundforming a portion of the fatty acid compound. The vitamin E compound caninclude one or more of alpha-tocopherol, beta-tocopherol,delta-tocopherol, gamma-tocopherol, alpha-tocotrienol, beta-tocotrienol,delta-tocotrienol, gamma-tocotrienol, alpha-tocopherol acetate,betatocopherol acetate, gamma-tocopherol acetate, delta-tocopherolacetate, alpha-tocotrienol acetate, beta-tocotrienol acetate,delta-tocotrienol acetate, gamma-tocotrienol acetate, alpha-tocopherolsuccinate, beta-tocopherol succinate, gamma-tocopherol succinate,delta-tocopherol succinate, alpha-tocotrienol succinate, betatocotrienol succinate, delta-tocotrienol succinate, gamma-tocotrienolsuccinate, mixed tocopherols, vitamin E TPGS, derivatives, analogs andpharmaceutically acceptable salts thereof.

In accordance with further aspects of the present invention, the fattyacid compound or derivative or analog thereof is cured to increaseviscosity to form the film. The bio-absorbable stand-alone film is curedusing at least one curing method selected from a group of curing methodsincluding application of UV light, application of heat, airflow, andreaction with a gas or chemical cross-linker. It should be noted thatcuring with respect to the present invention generally refers tothickening, hardening, or drying of a material brought about by heat,UV, or chemical means.

In accordance with further aspects of the present invention, thebio-absorbable stand-alone film further includes a therapeutic agent.The therapeutic agent can include an agent selected from the groupconsisting of antioxidants, anti-inflammatory agents, anti-coagulantagents, drugs to alter lipid metabolism, anti-proliferatives,anti-neoplastics, tissue growth stimulants, functional protein/factordelivery agents, anti-infective agents, imaging agents, anestheticagents, chemotherapeutic agents, tissue absorption enhancers,anti-adhesion agents, germicides, analgesics, prodrugs, and antiseptics.

In accordance with further aspects of the present invention, thetherapeutic agent is combined with the fatty acid compound prior toformation of the film, resulting in the therapeutic agent beinginterspersed throughout the film. Alternatively, the therapeutic agentis applied to the film in the form of a coating.

In accordance with further aspects of the present invention, thebio-absorbable stand-alone film is bioabsorbable. The bio-absorbablestand-alone film can further maintain anti-adhesive properties.

In accordance with further aspects of the present invention, the one ormore perforations form a regular pattern. At least one of the one ormore perforations may be a slit that is cut through the film from thefirst side through to the second side, or vice versa. The one or moreperforations may have regular shapes. At least one of the one or moreperforations may include a cavity for holding a liquid. The cavity mayinstead be adapted to hold one or more solid particles. Alternatively,the cavity may also be adapted to contain liquid with a solid particle.At least one of the one or more perforations may create an opening inthe film adapted to allow a body part to pass through the film. Theopening may be instead adapted to allow a surgical instrument to passthrough the film without damaging the film. The opening in the film maybe adapted to allow a fluid to pass through the film without damagingthe film. In accordance with a further aspect of the present invention,at least one of the one or more perforations is disposed on the firstside and/or the second side and does not pass completely through thefilm.

In accordance with further aspects of the present invention, thestand-alone film may further include a first coating disposed on thefirst side of the film. A second coating may be disposed on top of atleast a portion of the first coating. Alternatively, the second coatingmay be disposed on the second side of the film. The first coating and/orthe second coating may penetrate at least one of the one or moreperforations. The first coating may cover only a portion of the firstsurface or the entire first surface.

In accordance with further aspects of the present invention, thestand-alone film is sterilized. The stand-alone film may also bepackaged.

In accordance with another embodiment of the present invention, a methodof making a stand-alone film is introduced. The method includesproviding a non-porous stand-alone film having a first side and a secondside and formed of a non-polymeric cross-linked gel material formed atleast in part of a fatty acid compound or derivative or analog thereof.The method also includes forming at least one perforation in the film.

In accordance with one aspect of the present invention, the at least oneperforation is formed by cutting, carving, puncturing, or otherperforation forming action. In accordance with another aspect of thepresent invention, the at least one perforation penetrates completelythrough the film from the first side to the second side or vice versa.In accordance with yet another aspect of the present invention, the atleast one perforation is disposed on the first side or the second sideand does not pass completely through the film. In still another aspectof the present invention, the at least one perforation creates a cavityin the film.

In accordance with further aspects of the present invention, the methodfurther includes filling the cavity with a liquid, solid, gas orcombination thereof. The method may also include sterilizing andpackaging the film. The process of sterilizing and packaging the filmmay include providing a pouch having a non-permeable chamber and agas-permeable header, placing the film in the pouch, sealing the pouchalong the gas-permeable header, such that the non-permeable chamberremains accessible through the gas-permeable header, sterilizing thefilm with a sterilizing agent provided through the gas-permeable headerto the non-permeable chamber, sealing the film in the non-permeablechamber within the pouch, and optionally removing the header, leavingthe film packaged within the non-permeable chamber and sterilized. Inone embodiment, the sterilizing agent is selected from the groupconsisting of ethylene oxide (ETO) gas, radiation using gamma orelectron-beam radiation, steam, gas plasma and vaporized hydrogenperoxide.

In accordance with one aspect of the present invention, the methodoptionally includes purging the pouch with an inert gas prior to sealingthe non-permeable chamber and removing the gas-permeable header afterthe gas permeable header is sealed. The inert gas can comprise argon ornitrogen. In accordance with another aspect of the present invention,the method optionally includes exposing the pouch to vacuum conditionsand purging the pouch with an inert gas prior to sealing the gaspermeable header. The inert gas can comprise argon or nitrogen. Inaccordance with yet another aspect of the present invention, after thefilm is placed in the pouch, the method optionally includes purging thepouch with an inert gas and exposing the pouch to vacuum conditionsprior to sealing the gas permeable header. The inert gas can compriseargon or nitrogen.

In accordance with further aspects of the present invention, prior tosealing the gas permeable header, a desiccant, an oxygen scavenger, anoxygen barrier, or a combination thereof is added to the pouch. Thedesiccant is selected from the group consisting of silica gel, clay,molecular sieves, potassium permanganate, activated carbon, activatedalumina, and a water absorbable polymer.

In accordance with a further embodiment of the present invention, astand-alone film including a film structure having a first side and asecond side and formed of a non-polymeric cross-linked gel materialformed at least in part of a fatty acid compound or derivative or analogthereof and one or more depressions molded in the film structure on thefirst side and/or the second side is provided. At least one of the oneor more depressions may not pass completely through the film.Alternatively, at least one of the one or more depressions may penetratecompletely through the film from the first side to the second side, orvice versa. The stand-alone film may further include a coating disposedon the first surface and/or the second surface. The stand-alone film mayalso be sterilized and/or packaged.

In accordance with yet another embodiment of the present invention, amethod of making a stand-alone film is provided. The method includesproviding a compound in liquid form and being a non-polymeric materialformed at least in part of a fatty acid compound or derivative or analogthereof; applying the compound to a mold having one or more protrusions;and curing the compound to form the stand-alone film having a first sideand a second side.

In accordance with one aspect of the present invention, the one or moreprotrusions may create one or more depressions on the first side of thestand-alone film. Alternatively, the one or more protrusions may createone or more holes in the stand-alone film.

In accordance with further aspects of the present invention, the methodmay further includes providing a pouch having a non-permeable chamberand a gas-permeable header; placing the film in the pouch; sealing thepouch along the gas-permeable header, such that the non-permeablechamber remains accessible through the gas-permeable header; sterilizingthe film with a sterilizing agent provided through the gas-permeableheader to the non-permeable chamber; sealing the film in thenon-permeable chamber within the pouch; and optionally removing theheader, leaving the film packaged within the non-permeable chamber andsterilized. The sterilizing agent may be selected from the groupconsisting of ethylene oxide (ETO) gas, radiation using gamma orelectron-beam radiation, steam, gas plasma and vaporized hydrogenperoxide. After the film is placed in the pouch, the method may furtherinclude the steps of exposing the pouch to vacuum conditions and purgingthe pouch with an inert gas prior to sealing the gas permeable header.The inert gas may include argon or nitrogen. Alternatively, after thefilm is placed in the pouch, the method may further include the steps ofpurging the pouch with an inert gas and exposing the pouch to vacuumconditions prior to sealing the gas permeable header, where the inertgas includes argon or nitrogen.

BRIEF DESCRIPTION OF THE DRAWINGS

The present invention will become better understood with reference tothe following description and accompanying drawings, wherein:

FIG. 1A is an exemplary illustration of a bio-absorbable stand-alonefilm with cut through perforations forming a regular pattern accordingto one embodiment of the present invention;

FIG. 1B is an exemplary top-view illustration of a bio-absorbablestand-alone film with circular-shaped perforations forming an irregularpattern in accordance with one embodiment of the present invention;

FIG. 1C is an exemplary top-view illustration of a bio-absorbablestand-alone film with irregular-shaped perforations forming circularpatterns in accordance with one embodiment of the present invention;

FIG. 1D is an exemplary top-view illustration of a bio-absorbablestand-alone film with two cut through perforations forming a cross shapein accordance with one embodiment of the present invention;

FIG. 1E is an exemplary top-view illustration of a bio-absorbablestand-alone film with a perforation that creates an opening in the filmstructure in accordance with one embodiment of the present invention;

FIG. 1F is an exemplary top-view and blow-up view illustrations of abio-absorbable stand-alone film with a perforation that creates a cavityin the film in accordance with one embodiment of the present invention;

FIG. 1G is an exemplary top-view illustration of a bio-absorbablestand-alone film with perforations or depressions in accordance with oneembodiment of the present invention;

FIG. 1H is a side view illustration of the film in FIG. 1G when the filmis cut along the AA′ line in accordance with one embodiment of thepresent invention;

FIG. 2A shows a perforated stand-alone film conforming to athree-dimensional surface of a tissue, in accordance with one embodimentof the present invention;

FIG. 2B shows a perforated stand-alone film conforming to athree-dimensional surface of a tissue, in accordance with anotherembodiment of the present invention;

FIG. 3A is an exemplary side view illustration of a stand-alone filmcovered with a coating on one side of the film in accordance with oneembodiment of the present invention;

FIG. 3B is an exemplary side view illustration of a stand-alone filmcovered with a coating on both sides of the film in accordance with oneembodiment of the present invention;

FIG. 3C is an exemplary side view illustration of a stand-alone filmcovered with two coatings on one side of the film in accordance with oneembodiment of the present invention;

FIG. 3D is an exemplary side view illustration of a stand-alone filmcovered with a coating on one side of the film in accordance with oneembodiment of the present invention, where the coating penetrates aperforation formed within the film;

FIG. 3E is an exemplary side view illustration of a stand-alone filmcovered with a coating on one side of the film in accordance with oneembodiment of the present invention, where the coating covers adepression formed within the film;

FIG. 4 is a flow chart illustrating a method of coating a stand-alonefilm according to one embodiment of the present invention;

FIG. 5 is a flow chart illustrating an alternative method of coating astand-alone film according to one embodiment of the present invention;

FIG. 6 is a diagrammatic illustration of a packaging pouch with aheader, in accordance with one aspect of the present invention;

FIG. 7 is a flow chart illustrating a method of making a stand-alonefilm with one or more perforations according to one embodiment of thepresent invention;

FIG. 8 is a flow chart illustrating a method of packaging andsterilizing a bio-absorbable stand-alone film, in accordance with oneaspect of the present invention; and

FIG. 9 is a flow chart illustrating a method of making a stand-alonefilm with one or more depressions according to one embodiment of thepresent invention.

DETAILED DESCRIPTION

The present invention utilizes primarily fatty acids to form abio-absorbable stand-alone film. One or more perforations or depressionsare formed in the film. The phrase stand-alone film is used herein torefer to a film that does not require any material in addition to thefilm material to provide structure to the film. A medical device havinga coating of fish oil is not a stand-alone film because the coating offish oil relies on the device to provide structure to the film. Theperforations in the bio-absorbable stand-alone film allow the film toexpand and conform to a three-dimensional surface of a tissue even ininstances where the bio-absorbable film is non-elastic. The stand-alonefilms are bioabsorbable and cells may consume the breakdown products,fatty acid, short and long chain alcohol, and glyceride molecules.Bioabsorbable substances break down into substances or components thatdo not cause an inflammatory response and can be consumed by the cellsforming the body tissues. The perforations in the bio-absorbable filmalso help the biological absorption of the film by allowing body fluidsto contact a greater amount of surface area of the film compared to afilm without perforations. Furthermore, the resultant film is flexible,easy to handle, and relatively strong. The resultant film may be usedwith many surgical procedures when anti-adhesion is desirable for apre-determined amount of time.

FIGS. 1A through 9 illustrate example embodiments of a non-polymericbio-absorbable stand-alone film with perforations or depressions formedtherein and the method of making according to the present invention.FIG. 1A illustrates an exemplary bio-absorbable stand-alone film 100according to one embodiment of the present invention. The bio-absorbablestand-alone film 100 has a first side 102 and a second side 104. Thebio-absorbable stand-alone film 100 is flexible, to the extent that itcan be placed in a flat, curved, or rolled configuration within apatient. The stand-alone-film 100 is implantable, for both short termand long term applications. The bio-absorbable stand-alone film 100 hasa thickness in the range of 0.003 inches to 0.008 inches. One ofordinary skill in the art will appreciate that thicker films may be madefrom layering several bio-absorbable stand-alone films 100 together, orthe film itself may be made thicker. In other words, the thicker thebio-absorbable stand-alone film 100 is, the longer it takes for thebio-absorbable stand-alone film 100 to completely breakdown in thepatient's body. The bio-absorbable stand-alone film 100 may beconstructed to provide a barrier for a predetermined period of time,such as, but not limited to, a period of hours, a period of weeks, or aperiod of months.

Bio-absorbable stand-alone film 100 is made from fatty acids, such asomega-3 fatty acid, fish oil fatty acid, free fatty acid, triglycerides,esters of fish oil, or a combination thereof. Fish oil fatty acid mayfurther be one or a combination of arachidic acid, gadoleic acid,arachidonic acid, eicosapentaenoic acid, docosahexaenoic acid orderivatives, analogs, and pharmaceutically acceptable salts thereof.Free fatty acid may be one or more of butyric acid, caproic acid,caprylic acid, capric acid, lauric acid, myristic acid, palmitic acid,palmitoleic acid, stearic acid, loeic acid, vaccenic acid, linoleicacid, alpha-linolenic acid, gamma-linolenic acid, behenic acid, erucicacid, lignoceric acid, or derivatives, analogs and pharmaceuticallyacceptable salts thereof.

More specifically, the bio-absorbable stand-alone film 100 is formed ofa non-polymeric cross-linked gel derived from fatty acid compounds. Thefatty acids include omega-3 fatty acids when the oil utilized to formthe bio-absorbable stand-alone film is fish oil or an analog orderivative thereof. As liquid fish oil is heated, autoxidation occurswith the absorption of oxygen into the fish oil to create hydroperoxidesin an amount dependent upon the amount of unsaturated (C═C) sites in thefish oil. However, the (C═C) bonds are not consumed in the initialreaction. Concurrent with the formation of hydroperoxides is theisomerization of (C═C) double bonds from cis to trans in addition todouble bond conjugation. It has been demonstrated that hydroperoxideformation increases with temperature. Heating of the fish oil allows forcross-linking between the fish oil unsaturated chains using acombination of peroxide (C—O—O—C), ether (C—O—C), and hydrocarbon (C—C)bridges. The formation of the cross-links results in gelation of thefilm after the (C═C) bonds have substantially isomerized into the transconfiguration. The (C═C) bonds can also form C—C cross-linking bridgesin the glyceride hydrocarbon chains using a Diels-Alder Reaction. Inaddition to solidifying the film through cross-linking, both thehydroperoxide and (C═C) bonds can undergo secondary reactions convertingthem into lower molecular weight secondary oxidation byproductsincluding aldehydes, ketones, alcohols, fatty acids, esters, lactones,ethers, and hydrocarbons.

Accordingly, the film derived from fatty acid compounds, such as thoseof fish oil, includes a cross-linked structure of triglyceride and fattyacid molecules in addition to free and bound glycerol, monoglyceride,diglyceride, and triglyceride, fatty acid, anhydride, lactone, aliphaticperoxide, aldehyde, and ketone molecules. There are a substantial amountof ester bonds remaining after curing in addition to peroxide linkagesforming the majority of the cross-links in the film. The film degradesinto fatty acid, short and long chain alcohol, and glyceride molecules,which are all non-inflammatory and likewise consumable by cells in thesoft tissue to which the film is applied. Thus, the film isbioabsorbable.

The bio-absorbable stand-alone film 100 further provides a lubriciousand anti-adhesive surface against tissue. The bio-absorbable stand-alonefilm itself, in its substantially cured configuration, can provide aphysical anti-adhesion barrier between two sections of tissue. The useof the naturally occurring oil, such as fish oil, provides extralubrication to the surface of the film, which helps to reduce injury.With less injury, there is less of an inflammatory response, and lesshealing required. The oily surface of the film provides theanti-adhesion characteristics. One of ordinary skill in the art willappreciate that different oils will have different anti-adhesiveproperties, and the oils can be modified to be more liquefied or moresolid or waxy, as desired. Accordingly, the degree of anti-adhesiveproperties offered by the film can vary. The modification of the oilsfrom a more liquid physical state to a more solid, but still flexible,physical state is implemented through the curing process. As the oilsare cured, especially in the case of fatty acid-based oils such as fishoil, cross-links form creating a gel. As the curing process is performedover increasing time durations and/or increasing temperature conditionsand/or increasing UV output, more cross-links form transitioning the gelfrom a relatively liquid gel to a relatively solid-like, but stillflexible, gel structure.

In accordance with one aspect of the present invention, thebio-absorbable stand-alone film 100 can further include a therapeuticagent. The therapeutic agent can include an agent selected from thegroup consisting of antioxidants, anti-inflammatory agents,anti-coagulant agents, drugs to alter lipid metabolism,anti-proliferatives, anti-neoplastics, tissue growth stimulants,functional protein/factor delivery agents, anti-infective agents,imaging agents, anesthetic agents, chemotherapeutic agents, tissueabsorption enhancers, anti-adhesion agents, germicides, analgesics,prodrugs, and antiseptics. The therapeutic agent may be added to thefatty acid compound prior to forming a bio-absorbable stand-alone filmso that the therapeutic agent is interspersed throughout thebio-absorbable stand-alone film 100. Alternatively, the therapeuticagent may be applied to the bio-absorbable stand-alone film 100 to forma coating on a surface of the bio-absorbable stand-alone film after thefatty acid compound has formed a bio-absorbable stand-alone film.

In accordance with one aspect of the present invention, the therapeuticagent can include a vitamin E compound. The vitamin E compound mayinclude one or more of alpha-tocopherol, beta-tocopherol,delta-tocopherol, gamma-tocopherol, alpha-tocotrienol, beta-tocotrienol,delta-tocotrienol, gamma-tocotrienol, alpha-tocopherol acetate,beta-tocopherol acetate, gamma-tocopherol acetate, delta-tocopherolacetate, alpha-tocotrienol acetate, beta-tocotrienol acetate,delta-tocotrienol acetate, gamma-tocotrienol acetate, alpha-tocopherolsuccinate, beta-tocopherol succinate, gamma-tocopherol succinate,delta-tocopherol succinate, alpha-tocotrienol succinate,beta-tocotrienol succinate, delta-tocotrienol succinate,gamma-tocotrienol succinate, mixed tocopherols, vitamin E TPGS,derivatives, analogs and pharmaceutically acceptable salts thereof.

One of ordinary skill in the art will appreciate that the bio-absorbablestand-alone film of the present invention may be applied with othertherapeutic agents that are not listed above. These therapeutic agentsare added for healing purposes and not to provide structure to thebio-absorbable stand-alone film. Furthermore, the bio-absorbablestand-alone film can be formed in a manner that creates the potentialfor controlled long term release of a therapeutic agent, while stillmaintaining the benefits of the natural oil component of the film. Withthe present invention, and in the field of soft tissue applications, theuptake of the therapeutic agent is facilitated by the delivery of thetherapeutic agent to the cell membrane by the bio-absorbable stand-alonefilm.

The bio-absorbable stand-alone film 100 can be formed with manydifferent kinds of perforations or depressions. In accordance with oneaspect of the present invention, the bio-absorbable stand-alone film 100may have perforations 106 that are slits that are cut through the filmfrom the first side through to the second side or vice versa. Theperforations 106 form a regular pattern and are lined up with oneanother. The perforations 106 create slits with the same length. Thedistance between any two adjacent perforations is also the same.

In accordance with another aspect of the present invention, thestand-alone film may have perforations 108 that create small holes inthe film as shown in FIG. 1B. The perforations 108 have regularshapes-circles. The perforations may or may not be of the same size. Theperforations 108 may or may not form a regular pattern, but in thepresent example are positioned randomly.

In accordance with yet another aspect of the present invention, thestand-alone film may have perforations 110 as shown in FIG. 1C. Theperforations 110 have irregular shapes, but they form regular patternsin the form of circles.

In accordance with still another aspect of the present invention, thestand-alone film may have multiple perforations that intersect oroverlap with one another, such as shown in FIG. 1D. Perforations 112 aretwo slits that intersect each other. The slits are cut through from thefirst side 102 to the second side 104. Such an arrangement may allowinstruments to be inserted through the film when needed, but stillmaintains relative good separation of tissues from both sides of thefilm. Alternatively, the perforations may also allow a body part to passthrough the film when needed. An advantage of such perforations is thatthe perforations are adaptable to create openings of different sizes inthe film when needed but still allow the film to maintain its barrierfunction without creating a big opening in the film.

In accordance with yet another aspect of the present invention, thestand-alone film as shown in FIG. 1E may have a perforation 114 creatingan opening that is big enough to allow a surgical instrument to passthrough the film without damaging the film. The opening can also beadapted to allow a body part to pass through the film. The opening canalso be adapted to allow a fluid to pass through the film withoutdamaging the film.

In accordance with still another embodiment of the present invention,the stand-alone film as shown in FIG. 1F has perforations 116 thatinclude a cavity. The cavity has an opening 120 and a compartment 118.The opening 120 is on one surface of the film and the compartment 118 isbetween the first surface 102 and the second surface 104 of the film. Inother words, the cavity does not penetrate from one side of the film tothe other. The cavity may be used to hold a liquid in the compartment118. The cavity may also be used to hold one or more solid particles inthe compartment 1118. The cavity may hold both liquid and solidparticles.

In accordance with yet another embodiment of the present invention, thestand-alone film as shown in FIG. 1G has perforations 122 that are onlydisposed on the first side 102 and/or the second side 104 and do notpass completely through the film. The perforations 122 have regularshapes, but in this instance they do not form a regular pattern,although a pattern is possible. Alternatively, perforations 122 may beviewed as depressions 122 that form only on the surface and do notpenetrate through the film. FIG. 1H illustrates a side view from lineAA′ in FIG. 1G. FIG. 1H better illustrates that perforation/depression122 does not penetrate through one side of the film to the other.

One of ordinary skill in the art will appreciate that the presentinvention is not limited to the specific shapes and dimensions that aredisclosed herein and the illustrative embodiments are merely fordemonstration purposes only. Specifically, locations, patterns,placement, size, shape, depth, and other variations of the perforations,as would be understood by one of ordinary skill in the art are possible.

FIG. 2A illustrates how a perforated stand-alone film can be used toconform to a three-dimensional surface of a tissue in accordance withone embodiment of the present invention. Perforated stand-alone film 100has narrow slits 124 as perforations. The perforations 124 allow thestand-alone film 100 to expand in a manner that is not possible with theprior art non-elastic barrier films. Perforated stand-alone film 100 isable to conform to a three-dimensional surface of a tissue 126 withouttearing the film 100. This is achieved with the perforations 124 becausethey provide points or areas of expansion in an otherwise non-expandableor non-elastic material. The perforations 124 create openings in thefilm to allow body fluids to pass through the film and accelerate thebio-absorption process of the film by a patient's body.

FIG. 2B illustrates how a perforated stand-alone film can be used toconform to a three-dimensional surface of a tissue in accordance withanother embodiment of the present invention. Bio-absorbable stand-alonefilm 100 has perforations 124 that allow the film 100 to wrap around athree-dimensional surface 126 of a tissue. One of ordinary skill in theart will appreciate that there are many different perforationconfigurations and orientations that the stand-alone film 100 can haveso that it can conform to various tissue surfaces. The perforations in astand-alone film also accelerate the degradation of the film due to itsgreater amount of surface area compared to a stand-alone film of thesame size without any perforations. Hence, a perforated stand-alone filmis capable of conforming to a three-dimensional surface of a tissue, andcan also accelerate the bio-absorption of the film by a patient's body.

In accordance with further aspects of the present invention, thestand-alone film may have a coating on one side or both sides of thefilm. As shown in FIG. 3A, the stand-alone film 100 has a coating 130disposed on the first side 102 of the film. The coating 130 may cover aportion of the first surface or the entire first surface. In FIG. 3B,the stand-alone film 100 may have a second coating 132 disposed on thesecond surface 104, in addition to the first coating 130 disposed on thefirst surface 102. In this illustration, the second coating 132 coversonly a portion of the second surface 104, however one of ordinary skillin the art will appreciate that the second coating 132 may alternativelycover the entire second surface 104. In FIG. 3C, the stand-alone film100 has a second coating 132 disposed on top of at least a portion ofthe first coating 130. One of ordinary skill in the art will appreciatethat further coatings may be applied on the first surface 102 and/or thesecond surface 104 of the film 100. In FIG. 3D, the first coating 130penetrates a perforation 114. One of ordinary skill in the art willappreciate that the first coating can also be applied and not topenetrate the perforation 106. In FIG. 3E, the first coating 130 coversa depression 122 of the stand-alone film 100. One of ordinary skill inthe art will appreciate that the first coating 130 can alternatively notcover the depression 122 of the film 100 or the depression 122 may becovered by a different coating. One of ordinary skill in the art willappreciate that there are many different configurations of what portionsof the film are covered by a coating.

The types of coatings on the stand-alone film are not particularlylimited and can include, for example, biodegradable andnon-biodegradable coatings; polymeric coatings such as polyethylenecoatings; non-polymeric coatings, bioabsorbable coatings, and the like.Accordingly, coatings on the stand-alone film may be chemicallysensitive, or may include chemically sensitive components ortherapeutics. In accordance with one embodiment of the presentinvention, the coating can be in the form of a non-polymericcross-linked gel.

In one embodiment, the coatings can be any of the above-mentionedcoatings with or without one or more therapeutic agents. The therapeuticagents suitable for use in the invention are not particularly limited.The therapeutic agents can be hydrophilic, lipophilic, amphiphilic orhydrophobic, and can be dissolved in the bio-absorbable carrier, thesolvent or the bio-absorbable carrier and the solvent. The therapeuticagent can be any agent having therapeutic value when administered to asubject, for example, a mammal.

As utilized herein, the phrase “therapeutic agent(s)” refers to a numberof different drugs or agents available, as well as future agents thatmay be beneficial for use with the bio-absorbable stand-alone film ofthe present invention. The therapeutic agent can take a number ofdifferent forms including but not limited to anti-oxidants,anti-inflammatory agents, anti-coagulant agents, drugs to alter lipidmetabolism, anti-proliferatives, anti-neoplastics, tissue growthstimulants, analgesics, functional protein/factor delivery agents,anti-infective agents, anti-imaging agents, anesthetic agents,therapeutic agents, tissue absorption enhancers, anti-adhesion agents,anti-migratory agents, pro-healing agents, ECM/Protein productioninhibitors, germicides, antiseptics, proteoglycans, GAG's, gene delivery(polynucleotides), polysaccharides (heparin), rapamycin, melatonin,paclitaxel, a protein kinase C inhibitor, cerivastatin, cilostazol,fluvastatin, lovastatin, pravastatin or derivatives, analogs, prodrugsand pharmaceutically acceptable salts thereof, and any additionaldesired therapeutic agents such as those listed in Table 1 below. TABLE1 CLASS EXAMPLES Antioxidants Alpha-tocopherol, lazaroid, probucol,phenolic antioxidant, resveretrol, AGI-1067, vitamin E AntihypertensiveAgents Diltiazem, nifedipine, verapamil Antiinflammatory AgentsGlucocorticoids (e.g. dexamethazone, methylprednisolone), leflunomide,NSAIDS, ibuprofen, acetaminophen, hydrocortizone acetate, hydrocortizonesodium phosphate, macrophage-targeted bisphosphonates Growth FactorAngiopeptin, trapidil, suramin Antagonists Antiplatelet Agents Aspirin,dipyridamole, ticlopidine, clopidogrel, GP IIb/IIIa inhibitors, abcximabAnticoagulant Agents Bivalirudin, heparin (low molecular weight andunfractionated), wafarin, hirudin, enoxaparin, citrate ThrombolyticAgents Alteplase, reteplase, streptase, urokinase, TPA, citrate Drugs toAlter Lipid Fluvastatin, colestipol, lovastatin, atorvastatin,amlopidine Metabolism (e.g. statins) ACE Inhibitors Elanapril,fosinopril, cilazapril Antihypertensive Agents Prazosin, doxazosinAntiproliferatives and Cyclosporine, cochicine, mitomycin C, sirolimusAntineoplastics micophenonolic acid, rapamycin, everolimus, tacrolimus,paclitaxel, QP-2, actinomycin, estradiols, dexamethasone, methatrexate,cilostazol, prednisone, cyclosporine, doxorubicin, ranpirnas,troglitzon, valsarten, pemirolast, C- MYC antisense, angiopeptin,vincristine, PCNA ribozyme, 2-chloro-deoxyadenosine Tissue growthstimulants Bone morphogeneic protein, fibroblast growth factor Promotionof hollow Alcohol, surgical sealant polymers, polyvinyl particles, 2-organ occlusion or octyl cyanoacrylate, hydrogels, collagen, liposomesthrombosis Functional Protein/Factor Insulin, human growth hormone,estradiols, nitric oxide, delivery endothelial progenitor cellantibodies Second messenger Protein kinase inhibitors targetingAngiogenic Angiopoetin, VEGF Anti-Angiogenic Endostatin Inhibitation ofProtein Halofuginone, prolyl hydroxylase inhibitors, C-proteinaseSynthesis/ECM formation inhibitors Antiinfective Agents Penicillin,gentamycin, adriamycin, cefazolin, amikacin, ceftazidime, tobramycin,levofloxacin, silver, copper, hydroxyapatite, vancomycin, ciprofloxacin,rifampin, mupirocin, RIP, kanamycin, brominated furonone, algaebyproducts, bacitracin, oxacillin, nafcillin, floxacillin, clindamycin,cephradin, neomycin, methicillin, oxytetracycline hydrochloride,Selenium. Gene Delivery Genes for nitric oxide synthase, human growthhormone, antisense oligonucleotides Local Tissue perfusion Alcohol, H2O,saline, fish oils, vegetable oils, liposomes Nitric oxide Donor NCX4016 - nitric oxide donor derivative of aspirin, Derivatives SNAP GasesNitric oxide, compound solutions Imaging Agents Halogenated xanthenes,diatrizoate meglumine, diatrizoate sodium Anesthetic Agents Lidocaine,benzocaine Descaling Agents Nitric acid, acetic acid, hypochloriteAnti-Fibrotic Agents Interferon gamma - 1b, Interluekin - 10Immunosuppressive/Immunomodulatory Cyclosporine, rapamycin,mycophenolate motefil, Agents leflunomide, tacrolimus, tranilast,interferon gamma-1b, mizoribine Chemotherapeutic Agents Doxorubicin,paclitaxel, tacrolimus, sirolimus, fludarabine, ranpirnase TissueAbsorption Fish oil, squid oil, omega 3 fatty acids, vegetable oils,Enhancers lipophilic and hydrophilic solutions suitable for enhancingmedication tissue absorption, distribution and permeation Anti-AdhesionAgents Hyaluronic acid, human plasma derived surgical sealants, andagents comprised of hyaluronate and carboxymethylcellulose that arecombined with dimethylaminopropyl, ehtylcarbodimide, hydrochloride, PLA,PLGA Ribonucleases Ranpirnase Germicides Betadine, iodine, slivernitrate, furan derivatives, nitrofurazone, benzalkonium chloride,benzoic acid, salicylic acid, hypochlorites, peroxides, thiosulfates,salicylanilide Antiseptics Selenium Analgesics Bupivicaine, naproxen,ibuprofen, acetylsalicylic acid

Some specific examples of therapeutic agents useful in theanti-restenosis realm include cerivastatin, cilostazol, fluvastatin,lovastatin, paclitaxel, pravastatin, rapamycin, a rapamycin carbohydratederivative (for example as described in US Patent ApplicationPublication 2004/0235762), a rapamycin derivative (for example, asdescribed in U.S. Pat. No. 6,200,985), everolimus, seco-rapamycin,seco-everolimus, and simvastatin.

For drug loading, a therapeutic agent is combined with a fatty acidcompound prior to formation of the film in accordance with oneembodiment of the present invention. Hence, the resultant film has thetherapeutic agent interspersed throughout the film. For drug coating, atherapeutic agent is applied in the form of a coating on abio-absorbable stand-alone film. In one embodiment, a coating can beapplied by overlaying a drug-loaded fatty acid compound on abio-absorbable stand-alone film. After a therapeutic agent is dissolvedin an appropriate solvent, it is blended with a fatty acid compound toform a coating material. The solvent is evaporated prior to applying thecoating material as a coating on a bio-absorbable stand-alone film.Alternatively, the therapeutic agent may be blended directly into thefatty acid compound without the use of a solvent. The coating materialcan be, for example, sprayed or brushed onto a bio-absorbablestand-alone film. The coating material can also be cast directly on topof a bio-absorbable stand-alone film. The bio-absorbable stand-alonefilm with the coating material is heated or exposed to UV light to raisethe viscosity of the coating material beyond the gelation point andhence create a cross-linked gel coating on the bio-absorbablestand-alone film. Alternatively, the coating material can be left in astate of lower viscosity to preserve drug recovery rate or to alter therelease characteristics of the therapeutic agent used in the coatingmaterial.

In accordance with one embodiment of the present invention, a coatingcan be applied using a polyionic layer-by-layer (LBL) technique as shownby the flow chart in FIG. 4. After a bio-absorbable stand-alone film 100is provided (step 140), the bio-absorbable stand-alone film is contactedby a cationic solution (+charged) for a period of time (step 142), afterwhich the bio-absorbable stand-alone film is rinsed with deionized water(step 144). This results in the bio-absorbable stand-alone film beingadded with a layer of positively charged polyelectrolyte coating.Another layer of coating is then applied by contacting thebio-absorbable stand-alone film with an anionic solution (− charged) fora period of time (step 146), after which the bio-absorbable stand-alonefilm is again rinsed with deionized water (step 148). One or ordinaryskill in the art will appreciate that the concentration of thepolyelectrolytes can be varied. A therapeutic agent is coated onto thebio-absorbable stand-alone film by substituting the therapeutic agentfor one of the polyelectrolyte components of the LBL system (step 150).After the therapeutic agent is applied, the bio-absorbable stand-alonefilm may be rinsed with deionized water (step 152). Using this generalprocedure, a single drug layer can be coated on the surface of thebio-absorbable stand-alone film. Alternatively, a cappingpolyelectrolyte bilayer can be applied after the drug is coated onto thesurface of the bio-absorbable stand-alone film (step 154) and theprocedure (steps 148, 150, and 154) can be repeated several times tocreate multiple buried drug layers.

In accordance with yet another embodiment of the present invention, acoating can be applied by dipping a bio-absorbable stand-alone film in asolvent-therapeutic mixture to load the therapeutic agent onto thebio-absorbable stand-alone film as shown by the flow chart in FIG. 5. Atherapeutic agent is dissolved in an appropriate solvent (step 160). Thebio-absorbable stand-alone film is then dipped into the solution for aperiod of time to coat the surface of the film or to allow the film toswell and absorb some of the solution (step 162). The bio-absorbablestand-alone film is then removed (step 164) and the solvent in the filmis evaporated (step 166). Examples of solvents that may be used withthis method include, but are not limited to, ethanol and nMP.

One of ordinary skill in the art will appreciate that there are othermethods, such as spraying or painting, to apply a coating on astand-alone film other than the ones listed above. One of ordinary skillin the art will also appreciate that the coatings may or may not have atherapeutic agent incorporated therein. The stand-alone film may beinitially made without a therapeutic agent and later a coating with atherapeutic agent can be applied to the film. The types of therapeuticagents used in the film and the coatings may or may not be the same. Forexample, the perforated stand-alone film may have a longer acting agentprocessed into the film whereas the coatings may have a shorter actingagent.

In accordance with another aspect of the present invention, the film maybe sterilized or packaged. FIG. 6 is a diagrammatic illustration of apackaging pouch with a non-permeable chamber and a gas permeable header,where the pouch may be used to sterilize and/or package the film. Inaccordance with one aspect of the present invention, the packaging pouch200 is comprised of a non-permeable material 210 and gas permeableheader 220. The permeable material may be composed of a material such asTYVEK. The material is permeable to the extent of allowing permeation ofthe material by sterilization gases or products, as described herein.The packaging pouch has a chamber 230 capable of containing a variety ofstand-alone films. Appropriate stand-alone films for use with thepresent invention include, for example, implantable stand-alone films(i.e., stents, balloons, catheters, stand alone films, surgical mesh,and the like), surgical instruments (i.e., forceps, scalpels, retractorsand the like); and any other stand-alone film or instrument in need ofsterilization. In addition, the packaging pouch can be manufactured inany size and/or shape to contain any manner of stand-alone film orinstrument.

Referring again to FIG. 6, the packaging pouch has two sites to seal thepouch for sterilization. A first sealing site 240 is located at theopening of the pouch at the top of the gas permeable header 220. Asecond sealing site 250 is located at the bottom of the header 120.

One of ordinary skill in the art will appreciate that the packagingpouch 200 is merely one example illustrative embodiment of the packagingstructure that can be used in accordance with the present invention. Forexample, the header 220 can be implemented in a number of differentstructural embodiments, so long as the functional aspects of the headeras described herein, including its permeability to the desiredsterilization and inert gases, is maintained. The header 220 can beimplemented as a patch, access point, valve, or other gas permeableimplementation that performs in a similar manner as the header describedherein with regard to the sterilization methodology of the presentinvention. The header 220 can be disposed at any location on thepackaging that enables the method of sterilization.

Furthermore, the material 210 of the packaging can be made of a numberof different materials, so long as the functionality of beingnon-permeable, or substantially non-permeable to air is maintained. Forexample, plastics, composites, metals, and other materials can providethis functionality.

In addition, one of ordinary skill in the art will appreciate that thepresent invention is not limited with respect to the location of theseals (the first sealing site 240 and the second sealing site 250), andthe specific configuration illustrated and described herein. The sealscan be configured and located in a number of different implementations,so long as the seals provide the functionality of sealing off a chamberthat includes the gas permeable area (e.g. header 220) and thensubsequently sealing off the foil material 210 area of the packagingpouch 200 so that the sterilized contents of the packaging pouch 200 ismaintained in its sterile environment.

It should be noted that the sterilization occurs without substantiallydegrading the chemically sensitive stand-alone film, or any coatingsapplied to the stand-alone film or any therapeutic agents contained inthe coatings. In one embodiment, the sterilization does notsubstantially alter the coating through the loss of cis double bonds orby altering the degree of cross-linking of the coating.

FIG. 7 is a flow chart illustrating a method of creating a stand-alonefilm with one or more perforations in the film structure. In accordancewith one aspect of the present invention, a non-porous stand-alone filmhaving a first side and a second side and formed of a non-polymericcross-linked gel material formed at least in part of a fatty acidcompound or derivative or analog thereof is provided (step 302). Atleast one perforation (106, 108, 110, 112, 114, 116, 122) in then formedin the film (step 304). The at least one perforation (106, 108, 110,112, 114, 116, 122) can be formed by cutting, carving, or puncturing thefilm. The at least one perforation (106, 108, 110, 112, 114) cancompletely penetrate through the film from the first side to the secondside or vice versa. Alternatively, the at least one perforation (110,116, 122) can also be disposed on the first side and/or the second sideand does not pass completely through the film. The at least oneperforation (116) may create a cavity (118) in the film. The cavity(118) can be optionally filled with a liquid, solid, gas, or acombination thereof (step 306). The film can then be optionallysterilized and packaged (step 308).

FIG. 8 is flow chart illustrating the detailed steps of packaging andsterilizing a chemically sensitive stand-alone film with a sterilizingagent in step 308. In accordance with one aspect of the presentinvention, a chemically sensitive stand-alone film 100 is provided (step405). As used herein, the term “chemically sensitive” refers to anymaterial that may degrade and/or chemically react upon exposure to heat,steam, water, air or a chemical, or a combination thereof. A chemicallysensitive stand-alone film 100 can be a device in which one or morecomponents of the device may degrade and/or chemically react uponexposure to heat, steam, water, air or a chemical or a combinationthereof. Chemically sensitive components of the stand-alone film caninclude, for example, any material that comprises the device itself, aswell as any coatings and/or therapeutic agents comprised within thecoatings or the stand-alone film.

Still referring to FIG. 8, a packaging pouch 200 is provided (step 410).The stand-alone film 100 is then placed in the packaging pouch 200 (step415). In accordance with one aspect of the present invention, adesiccant, an oxygen scavenger, an oxygen barrier, or a combinationthereof may be added to the packaging pouch 200 before the pouch issealed. Suitable desiccants include, for example, silica gel, clay,molecular sieves, potassium permanganate, activated carbon, and activatealumina. Suitable oxygen scavengers include any inorganic material thatcan absorb oxygen, for example, iron oxide powders, sulfites,bisulfites, butylated hydroxytoluene (BHT), butylated hydroxyanisole(BHA), oxygen absorbable polymers enclosed in a pouch or added insidethe packaging (e.g., Chevron-Phillips Chemical Company's ethylenemethylacrylate cyclohexene methyl acrylated (EMCM) polymer or Ciba'sSpecialty Chemical's SHELFPLUS. Examples of oxygen barriers include, forexample, polyvinylidene chloride (PVDC)-coated films and polyvinylalcohol (PVOH). In one embodiment, the antioxidant and/or the desiccantmaterial may be incorporated into the material that is used to make thepouch. In another embodiment, the packaging pouch may be comprised of anantioxidant packaging material. Examples of antioxidant packagingmaterial include, for example, ethylene methylacrylate cyclohexenemethyl acrylated (EMCM) polymer (Chevron-Phillips), Ciba SpecialtyChemicals SHELFPLUS or other commercially available antioxidantpackaging material. In yet another embodiment, the packaging materialmay optionally be gas permeable.

In one embodiment, the pouch can be purged with inert gas (step 420),then submitted to vacuum conditions (step 425) before sealing of the gaspermeable header (step 440). In another embodiment, the pouch can besubmitted to vacuum conditions (step 430), then purged with an inert gas(Step 435) prior to the sealing of the gas permeable header (step 440).In yet another embodiment, the pouch containing the stand-alone film issealed at the opening of the pouch at the top of the header (step 440)upon placing the stand-alone film in the pouch. Upon sealing at thispoint, the packaging pouch is permeable to gasses and vapors in order toallow a sterilization process to occur.

The sealed pouch 200 containing the stand-alone film 100 is thensterilized with a sterilizing agent (step 445). Sterilizing agents arewell known in the art and can include, for example, normal ethyleneoxide (ETO) gas, cold ETO gas, aqueous glutaraldehyde solution,radiation using gamma or electron-beam radiation and steam, gas plasma,and vaporized hydrogen peroxide (VHP). In one particular embodiment, thesterilizing agent is vaporized hydrogen peroxide. In another particularembodiment, the sterilizing agent is cold ETO gas in which the ETO gasis administered at about 25-130° C. In another embodiment, the ETO gasis administered at about 37° C. Accordingly, a stand-alone film with acoating and optionally containing one or more therapeutic agents, uponsterilization with VHP or cold ETO gas, has diminished degradation ofthe stand-alone film, the coating and/or the one or more therapeuticagents. Furthermore, upon sterilization, the shelf life of thestand-alone film is extended.

Referring still to FIG. 8, after sterilization of the stand-alone film100 in the packaging pouch 200, the non-permeable chamber is then vacuumsealed (step 450) at point 250. In accordance with one exampleembodiment of the present invention, the packaging pouch 200 can bepurged with an inert gas, such as argon or nitrogen, prior to vacuumsealing of the non-permeable chamber at the second sealing point 250(step 446). The packaging pouch is vacuum sealed at the second sealingpoint 250. After the packaging pouch is vacuum sealed at sealing point250, the header can then be removed (step 460), if desired. Inaccordance with another embodiment of the present invention, the sterilepackaging pouch can be subjected to vacuum conditions (step 447), purgedwith an inert gas, for example, argon or nitrogen (step 448) and sealed(step 449) at the second sealing point 250. After the packaging pouch issealed, the header can then be removed (step 460), if desired.

FIG. 9 is a flow chart illustrating another method of the presentinvention, in the form of making a stand-alone film 100 with one or moredepressions 122. In accordance with one aspect of the present invention,a compound in liquid form and being a non-polymeric material formed atleast in part of a fatty acid compound or derivative or analog thereofis provided (step 502). The compound is then applied to a mold havingone or more protrusions (step 504). The compound is cured on the mold toform the stand-alone film 100 having a first side 102 and a second side104 (step 506). The one or more protrusions create one or moredepressions 122 on the first side or the second side of the stand-alonefilm. The one or more protrusions can alternatively create one or moreholes in the stand-alone film 100. The one or more protrusions may ormay not have the same size, shape, width, or height. Hence, it ispossible to use a mold to create a stand-alone film that has both adepression and a hole. Lastly, the film may be optionally sterilized andpackaged in step 308.

The perforated bio-absorbable stand-alone film 100 of the presentinvention may be used as a barrier to keep tissues separated to avoidadhesion. Application examples for adhesion prevention include abdominalsurgeries, spinal repair, orthopedic surgeries, tendon and ligamentrepairs, gynecological and pelvic surgeries, and nerve repairapplications. The perforated bio-absorbable stand-alone film may beapplied over the trauma site or wrapped around the tissue or organ tolimit adhesion formation. The addition of therapeutic agents to thebio-absorbable stand-alone films used in these adhesion preventionapplications can be utilized for additional beneficial effects, such aspain relief or infection minimization. Other surgical applications ofthe bio-absorbable stand-alone film may include using a bio-absorbablestand-alone film as a dura patch, buttressing material, internal woundcare (such as a graft anastomotic site), and internal drug deliverysystem. The perforated bio-absorbable stand-alone film may also be usedin applications in transdermal, wound healing, and non-surgical fields.The perforated bio-absorbable stand-alone film may be used in externalwound care, such as a treatment for burns or skin ulcers. The perforatedbio-absorbable stand-alone film may be used without any therapeuticagent as a clean, non-permeable, non-adhesive, non-inflammatory,anti-inflammatory dressing, or the perforated bio-absorbable stand-alonefilm may be used with one or more therapeutic agents for additionalbeneficial effects. The perforated bio-absorbable stand-alone film mayalso be used as a transdermal drug delivery patch when the perforatedbio-absorbable stand-alone film is loaded or coated with one or moretherapeutic agents. The perforations in the bio-absorbable stand-alonefilm allow the film to expand and conform to a three-dimensional surfaceof a tissue even if the bio-absorbable film is non-elastic. Theperforations in the bio-absorbable film also help the biologicalabsorption of the film by allowing body fluids to contact a greateramount of surface area of the film compared to a film withoutperforations.

The process of wound healing involves tissue repair in response toinjury and it encompasses many different biologic processes, includingepithelial growth and differentiation, fibrous tissue production andfunction, angiogenesis, and inflammation. The cross-linked gel used tomake the inventive bio-absorbable stand-alone film has been shown in ananimal model not to produce an inflammatory response, but still provideexcellent cellular overgrowth with little to no fibrous capsuleformation. Accordingly, the bio-absorbable stand-alone film provides anexcellent material suitable for wound healing applications.

The present invention provides methods for making bio-absorbablestand-alone films with perforations or depressions. The bioabsorbablenature of the stand-alone film results in the film being completelyabsorbed over time by the cells of the body tissue. There is nobreakdown of the bio-absorbable stand-alone film into components andsubstances that are known to be inflammatory and are eventuallydistributed throughout the body and in some instances disposed of by thebody, as in the case with biodegradable synthetic polymer surgicalfilms. In addition, the bio-absorbable stand-alone film surface can bemade to be either lubricious or anti-adhesive against body tissues. Thefatty acid derived cross-linked gel that makes up the bio-absorbablestand-alone film can be made to exhibit minimal to no anti-inflammatoryreaction to localized tissue or be made to exhibit non-inflammatoryproperties by use of one or more therapeutic agents in the film itself,or its coating. Selection of biological oil blends, with or withoutmedication, can be made to influence the amount of inflammation, whichin selected localized tissue applications can reduce, minimize or alternaturally occurring adhesions following blunt tissue dissection. Aperforated bio-absorbable stand-alone film made from fatty acidcompounds is flexible, easy to handle, and can be shaped easily as aresult of its improved conformability. One or more therapeutic agentsmay be applied to the perforated bio-absorbable stand-alone film or byuse of one or more therapeutic loaded coatings. Hence, thebio-absorbable stand-alone film not only provides improvedbio-mechanical performance to an inelastic biological film material, butfurther enhances the biological delivery mechanism when therapeuticagents are desired.

Numerous modifications and alternative embodiments of the presentinvention will be apparent to those skilled in the art in view of theforegoing description. Accordingly, this description is to be construedas illustrative only and is for the purpose of teaching those skilled inthe art the best mode for carrying out the present invention. Details ofthe structure may vary substantially without departing from the spiritof the invention, and exclusive use of all modifications that comewithin the scope of the disclosed invention is reserved.

1. A stand-alone film, comprising: a film structure having a first side and a second side and formed of a non-polymeric cross-linked gel material formed at least in part of a fatty acid compound or derivative or analog thereof, and one or more perforations provided in the film structure.
 2. The stand-alone film of claim 1, wherein the fatty acid compound comprises omega-3 fatty acid, fish oil fatty acid, free fatty acid, triglycerides, esters of fish oil, or a combination thereof.
 3. The stand-alone film of claim 2, wherein the fish oil fatty acid comprises one or more of arachidic acid, gadoleic acid, arachidonic acid, eicosapentaenoic acid, docosahexaenoic acid or derivatives, analogs and pharmaceutically acceptable salts thereof.
 4. The stand-alone film of claim 2, wherein the free fatty acid comprises one or more of butyric acid, caproic acid, caprylic acid, capric acid, lauric acid, myristic acid, palmitic acid, palmitoleic acid, stearic acid, oleic acid, vaccenic acid, linoleic acid, alpha-linolenic acid, gamma-linolenic acid, behenic acid, erucic acid, lignoceric acid, analogs and pharmaceutically acceptable salts thereof.
 5. The stand-alone film of claim 1, further comprising a vitamin E compound forming a portion of the fatty acid compound.
 6. The stand-alone film of claim 5, wherein the vitamin E compound comprises one or more of alpha-tocopherol, beta-tocopherol, delta-tocopherol, gamma-tocopherol, alpha-tocotrienol, beta-tocotrienol, delta-tocotrienol, gamma-tocotrienol, alpha-tocopherol acetate, beta-tocopherol acetate, gamma-tocopherol acetate, delta-tocopherol acetate, alpha-tocotrienol acetate, beta-tocotrienol acetate, delta-tocotrienol acetate, gamma-tocotrienol acetate, alpha-tocopherol succinate, beta-tocopherol succinate, gamma-tocopherol succinate, delta-tocopherol succinate, alpha-tocotrienol succinate, beta tocotrienol succinate, delta-tocotrienol succinate, gamma-tocotrienol succinate, mixed tocopherols, vitamin E TPGS, derivatives, analogs and pharmaceutically acceptable salts thereof.
 7. The stand-alone film of claim 1, further comprising a therapeutic agent, wherein the therapeutic agent comprises an agent selected from the group consisting of analgesics, antioxidants, anti-inflammatory agents, anti-coagulant agents, drugs to alter lipid metabolism, anti-proliferatives, anti-neoplastics, tissue growth stimulants, functional protein/factor delivery agents, anti-infective agents, imaging agents, anesthetic agents, chemotherapeutic agents, tissue absorption enhancers, anti-adhesion agents, germicides, analgesics, prodrugs, and antiseptics.
 8. The stand-alone film of claim 7, wherein the therapeutic agent is combined with the fatty acid compound prior to formation of the film, resulting in the therapeutic agent being interspersed throughout the film.
 9. The stand-alone film of claim 7, wherein the therapeutic agent is applied to the film in the form of a coating.
 10. The stand-alone film of claim 1, wherein the film is bioabsorbable.
 11. The stand-alone film of claim 1, wherein the one or more perforations form a regular pattern.
 12. The stand-alone film of claim 1, wherein at least one of the one or more perforations comprises a slit that is cut through the film from the first side through to the second side, or vice versa.
 13. The stand-alone film of claim 1, wherein the one or more perforations have regular shapes.
 14. The stand-alone film of claim 1, wherein at least one of the one or more perforations includes a cavity for holding a liquid.
 15. The stand-alone film of claim 1, wherein at least one of the one or more perforations creates an opening in the film adapted to allow a body part to pass through the film.
 16. The stand-alone film of claim 1, wherein at least one of the one or more perforations creates an opening in the film adapted to allow a surgical instrument to pass through the film without damaging the film.
 17. The stand-alone film of claim 1, wherein at least one of the one or more perforations creates an opening in the film adapted to allow a fluid to pass through the film without damaging the film.
 18. The stand-alone film of claim 1, wherein at least one of the one or more perforations is disposed on the first side and/or the second side and does not pass completely through the film.
 19. The stand-alone film of claim 1, wherein at least one of the one or more perforations has a cavity adapted to hold one or more solid particles.
 20. The stand-alone film of claim 1, wherein at least one of the one or more perforations is adapted to contain a liquid with a solid particle.
 21. The stand-alone film of claim 1, further comprising: a first coating disposed on the first side of the film.
 22. The stand-alone film of claim 21, wherein the first coating penetrates at least one of the one or more perforations.
 23. The stand-alone film of claim 21, wherein the first coating covers at least a portion of the first surface.
 24. The stand-alone film of claim 21, further comprising: a second coating disposed on the second side of the film.
 25. The stand-alone film of claim 24, wherein the first coating is materially different from the second coating.
 26. The stand-alone film of claim 21, further comprising: a second coating disposed on top of at least a portion of the first coating.
 27. The stand-alone film of claim 1, wherein the film is sterilized.
 28. The stand-alone film of claim 1, wherein the film is packaged.
 29. The stand-alone film of claim 1, wherein the one or more perforations allows the film to conform to a three-dimensional surface of a tissue without tearing the film.
 30. A method of making a stand-alone film, said method comprising: providing a non-porous stand-alone film having a first side and a second side and formed of a non-polymeric cross-linked gel material formed at least in part of a fatty acid compound or derivative or analog thereof; forming at least one perforation in the film.
 31. The method of claim 30, wherein the at least one perforation is formed by cutting.
 32. The method of claim 30, wherein the at least one perforation is formed by carving.
 33. The method of claim 30, wherein the at least one perforation is formed by puncturing.
 34. The method of claim 30, wherein the at least one perforation penetrates completely through the film from the first side to the second side, or vice versa.
 35. The method of claim 30, wherein the at least one perforation is disposed on the first side and/or the second side and does not pass completely through the film.
 36. The method of claim 30, wherein the at least one perforation creates a cavity in the film.
 37. The method of claim 36, further comprising: filling the cavity with a liquid, solid, gas or combination thereof.
 38. the method of claim 30, further comprising: sterilizing and packaging the film.
 39. The method of claim 38, further comprising: providing a pouch having a non-permeable chamber and a gas-permeable header; placing the film in the pouch; sealing the pouch along the gas-permeable header, such that the non-permeable chamber remains accessible through the gas-permeable header; sterilizing the film with a sterilizing agent provided through the gas-permeable header to the non-permeable chamber; sealing the film in the non-permeable chamber within the pouch; and optionally removing the header, leaving the film packaged within the non-permeable chamber and sterilized.
 40. The method of claim 39, wherein the sterilizing agent is selected from the group consisting of ethylene oxide (ETO) gas, radiation using gamma or electron-beam radiation, steam, gas plasma and vaporized hydrogen peroxide.
 41. The method of claim 39, wherein after the gas permeable header is sealed, the method further comprises the step of purging the pouch with an inert gas prior to sealing the non-permeable chamber and removing the gas permeable header.
 42. The method of claim 41, wherein the inert gas comprises argon or nitrogen.
 43. The method of claim 39, wherein after the film is placed in the pouch the method further comprises the steps of: exposing the pouch to vacuum conditions; and purging the pouch with an inert gas prior to sealing the gas permeable header.
 44. The method of claim 43, wherein the inert gas comprises argon or nitrogen.
 45. The method of claim 39, wherein after the film is placed in the pouch, the method further comprises the steps of: purging the pouch with an inert gas; and exposing the pouch to vacuum conditions prior to sealing the gas permeable header.
 46. The method of claim 45, wherein the inert gas comprises argon or nitrogen.
 47. The method of claim 39, wherein prior to the sealing the gas permeable header, a desiccant, an oxygen scavenger, an oxygen barrier, or a combination thereof is added to the pouch.
 48. The method of claim 47, wherein the desiccant is selected from the group consisting of silica gel, clay, molecular sieves, potassium permanganate, activated carbon, activated alumina, and a water absorbable polymer.
 49. A stand-alone film, comprising: a film structure having a first side and a second side and formed of a non-polymeric cross-linked gel material formed at least in part of a fatty acid compound or derivative or analog thereof; and one or more depressions molded in the film structure on the first side and/or the second side.
 50. The stand-alone film of claim 49, wherein at least one of the one or more depressions does not pass completely through the film.
 51. The stand-alone film of claim 50, wherein at least one of the one or more depressions penetrates completely through the film from the first side to the second side, or vice versa.
 52. The stand-alone film of claim 51, wherein the film is sterilized.
 53. The stand-alone film of claim 51, wherein the film is packaged.
 54. The stand-alone film of claim 49, further comprising: a first coating disposed on at least a portion of the first surface of the film.
 55. A method of making a stand-alone film, said method comprising: providing a compound in liquid form and being a non-polymeric material formed at least in part of a fatty acid compound or derivative or analog thereof; applying the compound to a mold having one or more protrusions; and curing the compound to form the stand-alone film having a first side and a second side.
 56. The method of claim 55, wherein the one or more protrusions creates one or more depressions on the first side of the stand-alone film.
 57. The method of claim 55, wherein the one or more protrusions creates one or more holes in the stand-alone film.
 58. The method of claim 55, further comprising: providing a pouch having a non-permeable chamber and a gas-permeable header; placing the film in the pouch; sealing the pouch along the gas-permeable header, such that the non-permeable chamber remains accessible through the gas-permeable header; sterilizing the film with a sterilizing agent provided through the gas-permeable header to the non-permeable chamber; sealing the film in the non-permeable chamber within the pouch; and optionally removing the header, leaving the film packaged within the non-permeable chamber and sterilized.
 59. The method of claim 58, wherein the sterilizing agent is selected from the group consisting of ethylene oxide (ETO) gas, radiation using gamma or electron-beam radiation, steam, gas plasma and vaporized hydrogen peroxide.
 60. The method of claim 58, wherein after the film is placed in the pouch the method further comprises the steps of: exposing the pouch to vacuum conditions; and purging the pouch with an inert gas prior to sealing the gas permeable header.
 61. The method of claim 60, wherein the inert gas comprises argon or nitrogen.
 62. The method of claim 58, wherein after the film is placed in the pouch, the method further comprises the steps of: purging the pouch with an inert gas; and exposing the pouch to vacuum conditions prior to sealing the gas permeable header.
 63. The method of claim 62, wherein the inert gas comprises argon or nitrogen. 